title: Neuronal Sirt3 protects against excitotoxic injury in mouse cortical neuron culture.
abstract: BACKGROUND
  Sirtuins (Sirt), a family of nicotinamide adenine nucleotide (NAD) dependent deacetylases, are implicated in energy metabolism and life span. Among the known Sirt isoforms (Sirt1-7), Sirt3 was identified as a stress responsive deacetylase recently shown to play a role in protecting cells under stress conditions. Here, we demonstrated the presence of Sirt3 in neurons, and characterized the role of Sirt3 in neuron survival under NMDA-induced excitotoxicity.
  
  
  RESULTS
  To induce excitotoxic injury, we exposed primary cultured mouse cortical neurons to NMDA (30 µM). NMDA induced a rapid decrease of cytoplasmic NAD (but not mitochondrial NAD) in neurons through poly (ADP-ribose) polymerase-1 (PARP-1) activation. Mitochondrial Sirt3 was increased following PARP-1 mediated NAD depletion, which was reversed by either inhibition of PARP-1 or exogenous NAD. We found that massive reactive oxygen species (ROS) produced under this NAD depleted condition mediated the increase in mitochondrial Sirt3. By transfecting primary neurons with a Sirt3 overexpressing plasmid or Sirt3 siRNA, we showed that Sirt3 is required for neuroprotection against excitotoxicity.
  
  
  CONCLUSIONS
  This study demonstrated for the first time that mitochondrial Sirt3 acts as a prosurvival factor playing an essential role to protect neurons under excitotoxic injury.
authors.affiliation: Department of Neurology, Veterans Affairs Medical Center, San Francisco, California, United States of America.
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Hua Fei
authors.initials: HF
authors.lastname: Lu
authors.forename: Conrad C
authors.initials: CC
authors.lastname: Alano
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology*; D019610:Cytoprotection / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D009243:NAD / Q000172:deficiency / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009498:Neurotoxins / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D056566:Sirtuin 3 / Q000378:metabolism*
chemical_list: D009498:Neurotoxins; C525046:Sirt3 protein, mouse; D009243:NAD; D016202:N-Methylaspartate; D011065:Poly(ADP-ribose) Polymerases; D056566:Sirtuin 3